Forebrain Overexpression of a Stress-Related Gene: Impact on Reactivity to Cocaine This project tests the hypothesis that the level of activity of a stress-related gene in the brain, the glucocorticoid receptor (GR) represents a molecular antecedent for increased susceptibility to drugs of abuse. Since the glucocorticoid receptor is a ligand-activated transacting factor that modulates many target genes implicated in emotional behavior and drug reward, and since it is known to mediate stress responsiveness and impact on mechanisms of neural plasticity, it represents a potential key molecular target for modulation of abuse liability. The proposed studies rely on two related mouse transgenic models we have developed: a) a constitutive GR overexpressor (GRov) with increased GR expression in the forebrain only. This animal shows altered emotional reactivity and increased sensitization to cocaine. It also shows significant alterations in the expression of genes implicated in substance abuse as well as neural plasticity genes such as growth factors; b) a new inducible/tissue-specific GR overexpressor (iGRov) in which GR overexpression in the forebrain can be controlled at various stages of development. We plan to determine whether the GRov animals, compared to their wild type littermates, exhibit alterations in hippocampal neurogenesis and morphology and/or changes in expression of neuroplasticity genes basally and after exposure to chronic cocaine. The same panel of genes used in the other three projects will be tested. Using iGRov, 'we plan to ascertain whether there are critical periods in development, includingpre- weaning and adolescence, during which lifelong responsiveness to cocaine can be altered. Finally we will ask whether a single neonatal exposure to fibroblast growth factor 2 (FGF2), which is known to enhance neurogenesis, can counteract the impact of GR overexpression on responsiveness to cocaine under control or social stress conditions. We will ascertain the neural changes associated with this manipulation in the wild type and transgenic animals. These studies will provide a mechanistic examination of the antecedents of substance abuse and will test specifically whether a balance of stress-related genes and growth factor-related genes determines susceptibility to psychoactive drugs and whether there are key developmental windows that impact on it.